Method for reduction of migraine headache pain

ABSTRACT

The invention is a method for reducing headache pain and symptoms associated with the onset or occurrence of headache in mammals. The method is performed by delivering an invertebrate presynaptic neurotoxin to a mammal extramuscularly (preferably at a localized, site of pain), or at a site in one or more muscles (preferably muscles of the face, cranium and neck). The presynaptic neurotoxins administered according to the invention are those neurotoxins that are known to produce a reversible, flaccid paralysis of muscle tissue in mammals. The preferred neurotoxin for use in the method of the invention is Botulinum toxin, particularly Botulinum toxin A.

RELATED PATENT APPLICATIONS

This is a continuation of application Ser. No. 08/343,331 filed on Nov. 21, 1994, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 81/240,973, filed May. 9, 1994, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to the pharmacological treatment of headache pain. More specifically, the invention relates to the reduction of pain associated with headaches through localized administration of a therapeutically effective dosage of pharmaceutically safe invertebrate exotoxin, in particular Botulinum toxin A.

2. History of the Prior Art

"Headache" is a term which encompasses a relatively vast spectrum of common symptoms and sometimes obscure causes. Headaches may be associated with emotional states such as depression and tension, as well as physical events such as muscular tension, neuralgia, neuropathy and vascular disturbances. Although a patient may experience more than one kind of headache pain, the various manifestations of headache are generally believed to have different pathological origins, (but see, Olosen, et al., Pain, 46:125-132, 1991 a model, albeit one unaccepted in the art, which proposes that tension headache shares a causal myofascial component with migraine!). For example, it is generally accepted in the art that the headache condition known as migraine is directly related to vascular changes and events attributable to contraction of the smooth muscles of blood vessels (see, e.g., Wolff, et al., "Headache and Other Head Pain", 1963; and Table 1(a), Row 1), while tension headache originates in skeletal (striated) muscular stress (Table 1(a), Row 2) and other headache pain stems principally from neurological disorders (see, e.g., Table 1(b)). Although therapies intended to alleviate headache symptoms are abundant, the efficacy of such treatments varies widely.

The most common types of headache, together with the perceived pathological origin of the pain and conventional methods for treatment, are summarized in Tables 1(a)-(b) below:

                  TABLE 1(a)                                                       ______________________________________                                         HEADACHES NOT PRIMARILY ASSOCIATED                                             WITH DISORDERS OF THE FACIAL AND CRANIAL NERVES                                        Presumed                Common                                         Type    Mechanism     Site      Treatment                                      ______________________________________                                         Migraine                                                                               Vascular dilation re-                                                                        Fronto    Ergot preparations,                            (vascular                                                                              sulting in changes to                                                                        temporal  analgesic, anti-in-                            head-   cerebral blood flow;                                                                         (uni- or  flammatory medi-                               ache)   possible hormonal                                                                            bilateral)                                                                               cations, and sero-                                     origin                  tonin modulators                               Tension Vascular      General-  Analgesic, anti-                               headache                                                                               disturbance and                                                                              ized      inflammatory, anti-                                    muscle spasm or         anxiety and anti-                                      fatigue (the latter is  depressant                                             not believed to be      medication                                             the                                                                            primary origin of                                                              pain)                                                                  Meninge-                                                                               Meningitis    General-  Treat the                                      al                    ized      underlying                                     irritation                      disease                                        Brain   Cancer        Varies    Treat the                                      tumor                           underlying disease                             Temporal                                                                               Arterial      Unilateral,                                                                              Cortico-                                       arteritis                                                                              disorders     temporal, steroids                                                             occipital                                                Traumatic                                                                              Head injuries result-                                                                        Varies    Varies depending                               headache                                                                               ing in subdural he-                                                                          depending on origin                                              matoma, dysa- on origin                                                        utonomic cephalal-                                                             gia or other disor-                                                            ders                                                                   ______________________________________                                    

                  TABLE 1(b)                                                       ______________________________________                                         HEADACHES PRIMARILY ASSOCIATED                                                 WITH DISORDERS OF THE FACIAL AND CRANIAL NERVES                                ______________________________________                                         Trigeminal                                                                              Trigeminal nerve,                                                                          Idiopathic, vascu-                                                                         Carbamazepine                                 neuralgia                                                                               unilateral  lar disturbances,                                                              multiple sclerosis,                                                            tumor                                                     Atypical facial                                                                         Unilateral or                                                                              Depressive, anxi-                                                                          Anti-depressant                               neuralgia                                                                               bilateral   ety states, idio-                                                                          and anti-anxiety                                                   pathic      medication                                    Orbitally                                                                               Unilateral in eye,                                                                         Idiopathic, paras-                                                                         Decongestant                                  related  cheek, ear, neck                                                                           inus disorders                                                                             nasal medication                              neuralgias                                                                     Tolosa-Hunt                                                                             Unilateral, mainly                                                                         Arteritis and                                                                              Corticosteroid                                Syndrome orbital     granulomatous                                                                              therapy                                                            lesions                                                   Reader's Unilateral, fronto-                                                                        Tumors,     Varies depend-                                paratrigeminal                                                                          temporal and                                                                               granulomatous                                                                              ing on                                        syndrome maxilla     lesions     origin                                        Postzoster syn-                                                                         Unilateral, Herpes zoster                                                                              Carbamazepine                                 drome    trigeminal divi-        and anti-                                              sions                   depressants                                   Costen's syn-                                                                           Unilateral, near                                                                           Loss of teeth,                                                                             Bite correction,                              drome    temporomandi-                                                                              rheumatoid  arthritis related                                      bular joints                                                                               arthritis   therapies                                     ______________________________________                                    

(Tables 1(a) and 1(b) are adapted from Harrison's Principles of Internal Medicine, 11th Ed., Chapter 6, Tables 6-1 and 6-2 (McGraw-Hill, 1987)).

One therapeutic modality for certain neuromuscular disorders which has begun to gain acceptance in recent years is the administration of invertebrate exotoxins in a pharmaceutically safe form. For example, serotype A of the Botulinum toxin has been recommended in the art for use for the treatment of certain diseases such as disorders of the extraocular muscles (e.g., comitant strabismus and nystagmus) as well as dystonias (involuntary contractions of facial muscle) (see, e.g., The New England Journal of Medicine, 324:1186-1194, 1991). The advantage of using Botulinum toxin A in this context is that it produces a reversible, flaccid paralysis of mammalian skeletal muscle, presumably by blocking the exocytosis of acetylcholine at peripheral, presynaptic cholinergic receptors, with limited activity at receptors in the central nervous system (Rabasseda, et al., Toxicon, 26:329-326, 1988). Additionally, Botulinum toxin A is not believed to result in degeneration of nervous or muscular tissue and has been approved for use in certain therapies by the U.S. Food and Drug Administration.

Botulinum toxin A is also presently being tested for its ability to cause the removal of hyperfunctional lines of the face. These tests have demonstrated that Botulinum toxin A may be administered into the musculature of the face without toxic effect to produce localized relaxation of skeletal muscle that lasts as long as six months (Blitzer, et al., Otolaryngol Head and Neck Surg., 119:1018-1023, 1993).

Other serotypes of the Botulinum toxin have been identified that have immunologically distinct phenotypes; i.e., serotypes B, C1, C2, D, F and G (Simpson, et al., Pharmacol.Rev., 33:155-188, 1981). All of the serotypes are believed to be proteins of about 150 kDa molecular weight that are comprised of two polypeptide chains linked by disulfide bridges. The shorter of the two chains is believed to be responsible for the toxicity of the toxin, while the longer of the two chains is believed to be responsible for the penetration of the toxin into nervous tissue. Although antigenically different to some extent, the Botulinum serotypes are believed to be similar in their pharmacological actions (Brin, et al., "Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology", Neurology, 40:1332-1336, 1990).

In addition, like serotype A, serotypes B and E of the Botulinum toxin have been linked to cases of botulism in humans. Thus, having the same pathological activity as serotype A, serotypes B and E can be reasonably expected to have the same therapeutic activity as serotype A in the method of the invention.

Other invertebrate toxins are known, or can reasonably be expected, to share the mode of action of Botulinum toxin and/or the toxin's ability to produce reversible, flaccid paralysis of muscles where the toxin is introduced. For example, serotypes A and E of the Botulinum toxin share a substantial degree of sequence homology with the Tetanus neurotoxin produced by Clostridium tetani (DasGupta, et al., Biochemie, 71:1193-1200, 1989). Further, although the tetanus neurotoxin typically acts on the central nervous system to produce rigid rather than flaccid muscle paralysis, at least one peptide digestion fragment of the tetanus toxin (fragment Ibc, which is produced as a papain cleavage product) have been shown to act peripherally to produce flaccid paralysis (Fedinic, et al., Boll.lst. Sieroter Milan, 64: 35-41, 1985; and, Gawade, et al., Brain Res., 334:139-46, 1985).

Another promising exotoxin-based therapy is the use of Staphylococcal alpha-toxin to stimulate the production of a naturally occurring brain component known as muscle-relaxing factor (MRF). Recently, researchers injected 1 microgram of Staphylococcal alpha-toxin into mice and detected elevated levels of MRF in serum and brain tissue. Reversible, flaccid paralysis of skeletal muscle in the injected mice was also observed (Harshman, et al., Infect.Immun., 62:421-425, 1994), indicating that S. alpha-toxin also shares the mode of action of Botulinum toxin.

Reversible, flaccid paralysis has also been observed following intrathecal injection of acylpolyamine toxins, anticholinergic, presynaptic neurotoxins that are produced in the venom of many invertebrates (Herold, et al., Anesthesiology, 77:507-512, 1992). In particular, two toxins (AR636 and AG489) from spiders Argiope aurantia and Agelenopsis aperta have been shown to produce motor inhibition at a dosage of 2 micrograms while 7 micrograms was an effective dosage to produce sensory inhibition. Despite the apparent effects of such exotoxins on motor and sensory activity in mammals, the use of such toxins in humans to date has been limited. Further, proposals for additional applications for exotoxins use have not included extramuscular applications generally or use in reduction of headache pain specifically.

SUMMARY OF THE INVENTION

The invention provides a method for reducing headache pain and symptoms in mammals, particularly humans. Specifically, the invention comprises administering a therapeutically effective amount of a pharmaceutically safe invertebrate presynaptic neurotoxin to a mammal. The preferred routes of administration are by extramuscular injection, such as into the perimuscular areas of the face, cranium and neck, as well as into localized sites of pain in these areas. Additional therapeutic benefits can be expected from administering the presynaptic neurotoxins of the invention into one or more striated muscles of the face, cranium and/or neck (including muscles of the shoulder region) muscles in the back.

The presynaptic neurotoxins of the invention will be those neurotoxins that can be administered to a mammal to produce localized paralysis of musculature that is reversible (although such paralysis need not necessarily be induced in the practice of the invention) and does not result in degeneration of muscle or nervous tissue. The preferred presynaptic neurotoxin of the invention is Botulinum toxin A.

Surprisingly, the method of the invention may not only be applied to reduce headache pain associated with muscle spasm or contraction, but may also be utilized to reduce headache pain associated with vascular disturbances, neuralgia and neuropathy. Even more surprisingly, it has been discovered that reduction of headache pain (particularly vascular headache pain) can be achieved through extramuscular administration of the presynaptic neurotoxins of the invention; i.e., without producing flaccid paralysis of muscle. The method may also be used to reduce symptoms associated with certain kinds of headache pain, such as the premonitory aura experienced by many migraine sufferers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a anatomical drawing depicting the musculature of the human face, cranium and neck. Common target sites (i.e., areas of localized headache pain) are circled; (1) is the frontal and glabella region, (2) is the temporal (right) region, and (3) is the suboccipital region.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A. PRESYNAPTIC NEUROTOXIN COMPOSITIONS FOR USE IN THE METHOD OF THE INVENTION

"Presynaptic neurotoxin" as used in this disclosure refers to both invertebrate toxins and biologically active peptide fragments of proteinaceous invertebrate toxins. The presynaptic neurotoxins of the invention will be those neurotoxins that are known to produce localized, flaccid paralysis of musculature in mammals that is reversible and does not result in degeneration of muscle or nervous tissue.

It will be appreciated, however, that the reduction of headache pain which may be achieved according to the method of the invention is apparently independent of the induction of flaccid muscular paralysis which the presynaptic neurotoxins of the invention will produce. Specifically, as described further below, reduction of headache pain may be achieved at dosages of presynaptic neurotoxin which are lower or higher than dosages required to produce flaccid paralysis of skeletal muscle and without introduction of the neurotoxin into muscle tissue.

The preferred presynaptic neurotoxin of the invention is Botulinum toxin. Serotype A of this toxin is commercially available and is presently supplied by Allergan, Inc. of Irvine, Calif. under the tradename "BOTOX and by Porton Products Ltd, of the United Kingdom under the tradename "DYSPORT". A pentavalent toxoid of all eight known Botulinum serotypes is also available as an investigational drug from the U.S. Center for Disease Control in Atlanta, Ga. Of these, the Botulinum A toxin preparations are most preferred for their known safety and efficacy.

Tetanus toxins for use as vaccines are also commercially available (from, for example, Lederle Laboratories of Wayne, N.J. under the tradename "TETANUS TOXOID PUROGENATED"). As discussed above, the Ibc fragment of the Tetanus toxin is believed to act peripherally and is therefore likely to be similar in its activity to Botulinum toxin. Therefore, the method of the invention will preferably encompass the use of pharmaceutically safe forms of the Ibc fragment of the Tetanus toxin rather than the use of intact Tetanus toxin.

Those of ordinary skill in the art will know, or can readily ascertain, how to obtain the presynaptic neurotoxins of the invention, including the Botulinum and Tetanus toxoids, in a pharmaceutically safe form; preferably, a form that is nontetragenic and does not induce a detectable immune response to the toxin antigen. For most of the presynaptic neurotoxins of the invention, pharmaceutical safety will be dose-dependent such that relatively low dosages of toxin will be "safe" as compared to dosages which are known to be sufficient to produce disease.

Preferably, the presynaptic neurotoxins of the invention will be administered as a composition in a pharmaceutically acceptable carrier. To that end, presynaptic neurotoxin compositions are prepared for administration by mixing a toxin the desired degree of purity with physiologically acceptable sterile carriers. Such carriers will be nontoxic to recipients at the dosages and concentrations employed. Ordinarily, the preparation of such compositions entails combining the presynaptic neurotoxin with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients. Such compositions may also be lyophilized and will be pharmaceutically acceptable; i.e., suitably prepared and approved for use in the desired application.

Most preferably, the presynaptic neurotoxin will be formulated in unit dosage form for ease of administration. For example, the presynaptic neurotoxin may be supplied as a sterile solution or lyophilized powder in a vial.

METHODS FOR ADMINISTRATION OF THE PRESYNAPTIC NEUROTOXINS OF THE INVENTION

Generally, the dose of presynaptic neurotoxin to be administered will vary with the age, presenting condition and weight of the mammal to be treated. The potency of the presynaptic neurotoxin will also be considered. Toxin potency is expressed as a multiple of the LD₅₀ value for a reference mammal, usually a mouse. Where a mouse is the reference mammal, one "unit" of toxin is the amount of toxin that kills 50% of a group of mice that were disease-free prior to inoculation with the toxin. For example, commercially available Botulinum toxin A typically has a potency such that one nanogram contains about 40 mouse units. The potency in humans of the Botulinum toxin A product supplied by Allergan, Inc. under the registered trademark "BOTOX" is believed to be about LD₅₀ =2,730 units.

Assuming a potency which is substantially equivalent to LD₅₀ =2,730 units, the presynaptic neurotoxin can be administered in a dose of up to about 1,000 units, although individual dosages of about 15-30 units are preferred and dosages of as low as about 2.5 to 5 units will have therapeutic efficacy. Generally, the presynaptic neurotoxin will be administered as a composition at a dosage that is proportionally equivalent to about 2.5 cc/100 units. Those of ordinary skill in the art will know, or can readily ascertain, how to adjust these dosages for presynaptic neurotoxin of greater or lesser potency.

Preferably, the lowest therapeutically effective dosage (i.e., the dosage which results in detection by the patient of a reduction in the occurrence and/or magnitude of headache pain experienced by the patient, even though other symptoms associated with the pain, such as the premonitory aura associated with vascular headache, may persist) will be injected. In the initial treatment, a low dosage may be administered at one site to determine the patient's sensitivity to, and tolerance of, the neurotoxin. Additional injections of the same or different dosages will be administered as necessary. For example, if headache pain predominates in the frontal cranial region (see, FIG. 1), the patient may receive up to 40 units in the glabella region, and may also receive up to 40 units of the neurotoxin in the mid-forehead region. For headache pain which predominates temporally, laterally and/or suboccipitally, the initial dosage (to be administered extramuscularly) will usually be somewhat lower; e.g., about 10 units per site, followed by up to 40 units per side.

For many indications (particularly vascular headaches), extramuscular injection will be the most efficacious route of administration as well as a route which avoids the risk of trauma to muscle tissue. Such injection may, for example, be made subcutaneously or, preferably, perivascularly (to produce infiltration of the neurotoxin into tissue at the target site). If possible, such injections will be made at a localized site of pain associated with the patient's presenting condition ("target site"); e.g., temporal, frontal and/or suboccipital sites in vascular headaches. Those of ordinary skill in the art will be familiar with such target sites and their pathological relationship to headache pain. For example, localized sites of pain known to be associated with the onset of migraine are the oculo-frontal-temporal area of the face and the forehead, with the former predominating in the early stages of migraine onset (see, e.g., Sjaastad, et al., Func.Neurol., 8:27-32, 1993 fronto-temporal pain is a typical trait of classical migraine!; this reference is incorporated herein by this reference to illustrate knowledge in the art regarding localized sites of headache pain). Common target sites are identified in FIG. 1.

The preferred target site for injection of the presynaptic neurotoxin will be in or near the or extramuscular regions, in particular, target sites of the face, cranium and neck (see, FIG. 1). Although the precise mechanism by which the method of the invention reduces headache pain is not known, it is believed that the efficacy of the method is not necessarily dependent on whether muscle spasm or strain is present in the patient or causally related to the headache pain experienced by the patient.

For example, as shown in the data presented in the Examples, the method of the invention was effective in reducing headache pain even in persons who only received an extramuscular injection of presynaptic neurotoxin. Moreover, reduction of headache pain was unexpectedly observed even in patients whose pain was causally related to vascular or neurological components; e.g., classical migraine, trigeminal neuralgia and trauma headache. However, those of ordinary skill in the art will recognize that additional therapeutic benefits may be achieved through introduction of the presynaptic neurotoxins of the invention into musculature (particularly in the back) where muscle spasm or strain is present.

The most preferred target sites are the bilateral temporal, frontal, glabella, and suboccipital areas of the face (see, FIG. 1 ). The corrugator, procerus, temporal and frontalis muscles are also suitable sites for introduction of the presynaptic neurotoxins of the invention. Localized paralysis in any injected muscle can be monitored visually, by the patient's description of post-injection mobility at the target site musculature, as well as by electromyographical signals obtained at the time of administration of the neurotoxin. For introduction into extramuscluar target sites, the presynaptic neurotoxins of the invention will conveniently be administered by injection.

For intramuscular injections, to ensure that the presynaptic neurotoxin is delivered to the target site without substantial systemic distribution, the use of electromyographical ("EMG") injection is recommended. A preferred technique for EMG injection is to introduce the presynaptic neurotoxin through a monopolar hollow bore needle (commonly, one which is coated with a non-stick surface such as "TEFLON", a trademarked product of DuPont Nemours, of Massachusetts). The needle is placed through the skin and into the target site of a muscle, preferably at a neuromuscular junction. Once the needle has been inserted, the most active site of the muscle can be determined by observation of the EMG signal. Those of ordinary skill in the art will know of, or can readily ascertain, other suitable techniques for administering EMG injections.

The injections will be repeated as necessary. As a general guideline, Botulinum toxin A administered into or near muscle tissue according to the method of the invention has been observed to produce flaccid paralysis at target site muscles for up to about 3 to 6 months. Reduction of headache pain in patients who received the presynaptic neurotoxins of the invention extramuscularly has also persisted for extended periods of time. However, Botulinum A toxin in particular is expected to be most effective when administered according to the method of the invention at about 3 month intervals.

The invention having been fully described, examples illustrating its practice are set forth below. These examples should not, however, be considered to limit the scope of the invention, which is defined by the appended claims.

In the examples, the abbreviation "min" refers to minutes, "hrs" and "h" refer to hours, "mo" and "mos" refers to months, "yr" and "yrs" refer to years, and measurement units (such as "ml") are referred to by standard abbreviations. Also, "F" refers to female and "M" refers to male. Further, in Examples I and II, the following symbols indicate trademarks of the companies listed below:

▪ Trademarked product of Sandoz Pharmaceuticals.

▪▪ Trademarked product of Bristol-Myers Laboratories

▪▪▪ Trademarked product of Stuart Pharmaceuticals

▪▪▪▪ Trademarked product of Syntex Pharmaceuticals

▪▪▪▪▪ Trademarked product of Merck, Sharp & Dohme Pharmaceuticals

▪▪▪▪▪▪ Trademarked product of Schering Drug

• Trademarked product of Winthrop-Breon

∘ Trademarked product of Eli Lilly Pharmaceuticals

▪ Trademarked product of Roche Products

† Trademarked product of DuPont

▪ Trademarked product of Ayerst Pharmaceuticals

Trademarked product of Cerenex Pharmaceuticals

EXAMPLE l ADMINISTRATION OF BOTULINUM TOXIN A TO REDUCE HEADACHE PAIN IN HUMANS

Over a period of 6 months, 162 patients received 1 to 2 injections of Botulinum toxin A ("BOTOX"), reconstituted with saline to a concentration of 2.5 cc/100 units. The toxin was administered intramuscularly by EMG injection into the frontalis, corrugator, procerus and/or platysma muscles of the face. The patients were participants in a clinical trial of the use of Botulinum toxin A to temporarily remove facial wrinkles.

Of the patients who received the injections, 11 spontaneously reported a prior case history of headache pain ("headache group" patients). Of the headache group patients, 5 had a prior history of migraine, 1 had previously been diagnosed as having trigeminal neuralgia, and the remainder suffered from frequent "tension" headaches (i.e., at an occurrence of at least 3 times a week). Of the patients reporting a prior history of migraine, two reported that they were suffering from an attack at the time that the injection was administered. One of these patients was experiencing headache pain, while the other was experiencing premonitory symptoms of migraine; i.e., a visual aura. The patient with trigeminal neuralgia had previously been treated pharmacologically without substantial reduction of her symptoms.

All of the 11 patients in the headache group reported that they were either free of headaches or suffered substantially reduced headache pain (as evaluated subjectively by the patient) for periods of up to 6 months following treatment. The two patients who had reported that they were experiencing migraine symptoms at the time of treatment reported that the symptoms completely dissipated after 1 to 11/2 hrs.

Additional details of the case history, treatment, and post-treatment history of patients within the headache group who agreed to the provide such information are tabulated below in Table 2.

                                      TABLE 2                                      __________________________________________________________________________                                 Dosage and                                                                             Post                                       Age/                                                                              Presenting         Site of                                                                              Frequency                                                                              Injection                                  Sex                                                                               Condition                                                                               Prior Treatment                                                                          Delivery                                                                             of Injection                                                                           Condition                                  __________________________________________________________________________     42/F                                                                              Periodic migraines                                                                      CAFERGOT▪                                                                      Corrugator                                                                           12 units, 1 time;                                                                      No migraine                                   over 7-8 years                                                                          (ergotamine tartrate)                                                                    and procerus                                                                         15 units, 1 time.                                                                      pain for 7 mos                                                         Administered                                                                   over a 7 mos                                                                   interval.                                          42/F                                                                              Severe migraine, at                                                                     STADOL▪ ▪ (butor-                                                    Corrugator                                                                           16 units, 3                                                                            No migraine                                   about 2 week inter-                                                                     phanoltartrate)                                                                          and   times; 22 units,                                                                       pain for 3                                    vals since age 8                                                                        analgesic and                                                                            procerus                                                                             2 times.                                                                               mos.; one attack                              years    ELAVIL▪ ▪ ▪ 4                                                    Administered                                                                           ended 1 h,                                             times/day (anti-                                                                               over a 3                                                                               15 min                                                 depressant) and mos interval.                                                                          after dosing;                                          NAPROSYN▪ ▪ ▪ ▪                                                on 2nd occasion                                        at 500 mg/day           pain at end of                                         (anti-                  migraine cycle                                         inflammatory)           ended 30 min                                                                   after dosing                               38/F                                                                              Migraine sufferer,                                                                      No detail available                                                                      Corrugator                                                                           16 units, 1 time;                                                                      No migraine                                   no detail available                                                                               and   20 units, 1 time.                                                                      pain for more                                 re history         procerus                                                                             Administered                                                                           than six                                                               over about a                                                                           months                                                                 one mos                                                                        interval.                                          44/F                                                                              Tension headache                                                                        Acetaminophren                                                                           Corrugator,                                                                          16 units, 1 time                                                                       No headache                                   about 1/week for 10                                                                     (500 mg)  procerus                                                                             to the frontalis;                                                                      pain for 3                                    years. Most pain in                                                                               and   15 units, 1 time                                                                       months in left                                left temporal region.                                                                             frontalis                                                                            to the  temporal                                      Some joint pain on       corrugator                                                                             region. Joint                                 left side of jaw.        and procerus.                                                                          pain also re-                                                          Administered                                                                           lieved but pain                                                        at the same                                                                            occurred once                                                          time.   in the right                                                                   temporal                                                                       region                                     36/F                                                                              Daily tension head-                                                                     INDOCIN   Corrugator                                                                           16 units, 1 time                                                                       Some                                          aches of moderate                                                                       SR▪ ▪ ▪ ▪ ▪                            and           reduction of                                  to severe intensity                                                                     (75 mg)   procerus      pain                                          for more than 4                                                                         (indomethacin)                                                        years                                                                       47/F                                                                              Migraine at about                                                                       Analgesic tablets,                                                                       Corrugator                                                                           16 units, 2                                                                            No migraine                                   1-2 month intervals                                                                     VANCEN-   and   times to the                                                                           for 4 months.                                 and tension or sinus                                                                    ASE▪ ▪ ▪ ▪ ▪                  ▪                                                                             procerus                                                                             corrugator and                                                                         Other                                         headache daily                                                                          (beclo-         procerus; 12                                                                           headache                                               methasone)      units, 1 time to                                                                       pain down to                                                           the corrugator                                                                         about 3 day                                                            and procerus;                                                                          intervals                                                              20 units, 1 time                                                               to the bilateral                                                               temporal                                                                       areas. Admini-                                                                 stered over a 4                                                                mos interval.                                      41/F                                                                              Migraine at about 6                                                                     Codeine   Corrugator                                                                           1 dose of                                                                              No migraine                                   week intervals with                                                                               and   16 units.                                                                              for one month                                 premonitory aura   procerus      but other                                     and tension head-                headache                                      ache at about                    pain more fre-                                1/week intervals                 quent                                      40/F                                                                              Tension headaches                                                                       Aspirin   Corrugator                                                                           15 units, 3                                                                            No headache                                   several times a    and   times   pain for one                                  week               procerus                                                                             corrugator and                                                                         year                                                             and   procerus; 20                                                             frontalis                                                                            units, 1 time,                                                                 frontalis; 10                                                                  units, bilateral                                                               temporal areas.                                                                Administered                                                                   over a 6 mos                                                                   interval.                                          58/F                                                                              Tension headache                                                                        Ibuprofen Corrugator,                                                                          10 units, 1 time                                                                       No headache                                   associated with    procerus                                                                             to corrugator                                                                          pain for                                      premenstrual cycle and   and procerus;                                                                          approximately                                                    frontalis                                                                            16 units, 2 times                                                                      3 mos.                                                                 to corrugator and                                                              procerus; 16                                                                   units, 1 time to                                                               frontalis; 20                                                                  units, 1 time to                                                               frontalis.                                                                     Administered                                                                   over a 5 month                                                                 period.                                            __________________________________________________________________________

Additional patients ("pt.") were treated using the method described in Example I, with particular emphasis on extramuscular injections of the Botulinum A toxin in the frontal, suboccipital and temporal regions of the face. The only adverse effect of the injection reported by any patient was soreness at the injection site, particularly at intramuscular injection sites. The results of the treatment received by each patient are reported in Table 3, below.

                                      TABLE 3                                      __________________________________________________________________________     Age/                                                                           Sex                                                                               Prior Treatment                                                                           Site of Delivery                                                                           Presenting Condition                                                                        Post Injection Condition                __________________________________________________________________________     42/F                                                                              ▪Cafergot                                                                       12 units, Glabella 5/7/93;                                                                 Has had severe headaches                                                                    As of 11/93: the pt.                                  5 units, Glabella 10/29/93                                                                 (possibly of migraine origin)                                                               was quoted as saying:                                             for the last 7-8 years without                                                              "Since I received the                                             premonitory symptoms.                                                                       BOTOX, almost 6                                                   Bright lights, loud noises,                                                                 months ago, my                                                    dairy products intensify pain.                                                              migraines  headaches!                                                          have been completely                                                           eliminated."                                                                   NOTE:                                                                          Most of the pt.'s                                                              corrugator muscle                                                              function returned 3                                                            months after the                                                               injection, although pt.                                                        had has not had                                                                headache pain for                                                              another 3 after muscle                                                         function returned.                      42/F                                                                              Stadol▪ ▪ now. In                                                     16 units, Glabella 10/23/92;                                                               Onset - 8 years of age;                                                                     Pt. had a migraine                         past - Cafergot▪                                                                16 units, Glabella 6/11/93;                                                                Cheese/Chocolate/Stress -                                                                   when treated on                                       10 units, Forehead 6/30/93;                                                                set off headaches (possibly                                                                 4/13/94. Within 30                                    6 units (booster), Glabella                                                                of migraine origin);                                                                        min. nausea ended;                                    6/30/93;    Symptoms: Pain "severe",                                                                    within 1.5 hours the                                  22 units, suboccipital (left                                                               nausea;      migraine pain ended.                                  side) 1/13/94;                                                                             Frequency: Every 2 weeks                                                                    No migraine headache                                  22 units, suboccipital (right                                                              until head injury, 7/94.                                                                    pain for 3 months after                               side) 4/13/94;                                                                             Frequency increased, with                                                                   each treatment.                                       20 units each, Glabella and                                                                additional parietal and                                                                     NOTE:                                                 Bilateral Temporal 6/10/94;                                                                suboccipital pain not                                                                       Flaccid paralysis of                                  10 units each, Left parietal,                                                              experienced in past migraine                                                                the corrugator and                                    left and right suboccipital                                                                history.     procerus muscles was                                  9/14/94;                 achieved on June 11,                                  10 units left suboccipital                                                                              1993. However,                                        and 20 units bilateral   elimination of pain was                               temporal 9/30/94         not achieved until                                    (Forehead, bilateral     injections given on                                   temporal and suboccipital                                                                               6/30/93. Elimination of                               injections not into muscle).                                                                            headache pain in the                                                           left suboccipital region                                                       achieved on 1/13/94;                                                           elimination of pain in                                                         the right suboccipital                                                         region achieved                                                                4/13/94, Pain                                                                  associated with head                                                           injury relieved within                                                         several hours of                                                               injection. However, pt.                                                        reports occasional                                                             occurrence of nausea.                   38/F                                                                              4-5 ibuprofen and                                                                         16 units, Glabella 3/25/94;                                                                Pt. began experiencing                                                                      As of receiving first                      other drugs                                                                               20 units, Glabella 4/15/94                                                                 frequent severe headache                                                                    injection, pt has not                                 16 units, Glabella 6/29/94                                                                 pain (possibly of migraine                                                                  had any headache                                                  origin) without premonitory                                                                 pain for about 6                                                  symptoms about 9 years                                                                      months. However, the                                              ago.         second injection was                                                           required to induce                                                             flaccid paralysis of                                                           muscle.                                 44/F                                                                              Acetomenaphin,                                                                            15 units, Glabella 2/18/94;                                                                Suffers severe headaches                                                                    Pt. had one headache                       500 mg.    16 units, Forehead 2/18/94;                                                                (possibly of migraine origin)                                                               in the right temporal                                 23 units, Forehead 9/9/94                                                                  about once a week for last                                                                  area in March, 1994.                                  (Forehead injection not into                                                               10 years. Intensity ranges                                                                  Otherwise, for about 7                                muscle).    from moderate to extreme.                                                                   months following the                                              Most headaches appear to                                                                    first set of injections,                                          be centered in the left                                                                     pt. did not experience                                            temporal area. No                                                                           any headache pain                                                 premonitory symptoms. Pt.                                                                   over her forehead and                                             also reported experiencing                                                                  upper frontal cranial                                             some pain in the temporal                                                                   region. However, pt.                                              mandibular joint area.                                                                      reported having                                                                premonitory nausea                                                             and other symptoms of                                                          migraine.                                                                      TM Joint pain also                                                             relieved on left side of                                                       face.                                   36/F                                                                           25 Elavil▪ ▪ ▪ ▪                          16 units, Glabella 3/25/94                                                                Pt. suffers from moderate to                                                               Pt. described condition                                 mg. 4 times a          severe headaches daily. Pt                                                                  as being a "minor                          day;                   was diagnosed with chronic                                                                  improvement" of her                        Naprosyn▪ ▪ ▪ ▪                                   tension headaches 4 years                                                                  headache pain.                                          500 mg. daily;         ago by a neurologist. Pt.                               Indocin▪ ▪ ▪ ▪ ▪:                                   had been in several car                                 mg.                    accidents before                                                               experiencing the diagnosed                                                     condition. Pt. does not                                                        experience premonitory                                                         symptoms.                                            47/F                                                                              Aspirin;Vancen-                                                                           16 units, Glabella 1/27/94;                                                                Onset: 12 years of age,                                                                     Pt. reports that she                       ase▪ ▪ ▪ ▪ ▪                 ▪                                                                               12 units, Glabella 4/15/94;                                                                Precipitating Events: Strong                                                                has not had a severe                                  20 units, Crow's 4/15/94;                                                                  odor/heat/bright                                                                            ("migraine") headache                                 15 units, Glabella 8/24/94                                                                 lights/noises/being                                                                         since the treatment                                   (Crow's feet area injection                                                                startled/and hunger. Hands                                                                  began. Pt. also                                       not into muscle)                                                                           can become cold or tingling                                                                 reports that she has                                              sensations can occur.                                                                       "general" headache                                                Becomes nauseated.                                                                          pain only "sporadically"                                          Occurrence: "Migraine"                                                                      (e.g., decreased in                                               (severe) headaches - once                                                                   frequency from daily to                                           every 1-2 months. Other                                                                     approx. every 3 days).                                            type of "general" (tension)                                                    headache occurs daily.                                                         Relief: Vanconase Inhaler                                                      (for vasomotor rhinitis)/quiet,                                                dark room.                                           44/F                                                                              Aspirin    16 units, Glabella 4/15/94;                                                                Onset: early 30's. Tension                                                                  During the period                                     12 units, Glabella 5/27/94                                                                 headaches nearly every                                                                      between receiving the                                             morning. On a scale of 1-                                                                   first and second                                                  10, patient rated her                                                                       injections, pt. reports                                           headaches 3-4.                                                                              that she did not have                                                          any headache pain.                                                             Pt. did have a                                                                 headache on the                                                                morning of 5/27/94                                                             (date of 2nd injection)                                                        which was relieved by                                                          aspirin.                                41/F                                                                              Codeine tablets                                                                           18 units, Glabella 4/15/94                                                                 Onset: 12 years of age after                                                                Pt. reports that she did                                          head trauma. Diagnosed as                                                                   not experience any                                                having migraine headaches                                                                   migraine headache                                                 triggered by certain smells                                                                 pain for about 3                                                  and muscle spasms. Has                                                                      months, but is having                                             premonitory aura which lasts                                                                more frequent tension                                             for 20-25 minutes.                                                                          headaches.                                                        Headache pain occurs with                                                                   Pt.'s ability to contract                                         hot flashes, visual                                                                         injected muscles                                                  disturbances and excessive                                                                  returned before she                                               perspiration. Occurs                                                                        experienced another                                               approximately every 6                                                                       migraine headache.                                                weeks. Pt. also reports have                                                                Note: Patient came                                                less frequent tension                                                                       into office with                                                  headaches.   migraine headache.                                                             Within 1 hour after                                                            injection, the                                                                 symptoms were                                                                  relieved.                               40/F                                                                              Aspirin    10 units, Crow's feet area                                                                 Frequent headaches                                                                          Since injections given                                10/6/93;    (probably tension                                                                           over the course of last                               15 units, Glabella 10//93;                                                                 headaches).  6 months, pt. reports                                 20 units, Forehead 10/6/93;                                                                             that she has not had                                  20 units, Crow's feet    any headache pain for                                 4/25/94;                 approximately 1 year.                                 8 units, Chin 4/25/94;                                                         20 units, Crow's feet                                                          5/27/94;                                                                       15 units, Crow's feet                                                          7/15/94                                                                        (Forehead and Crow's feet                                                      area injections not into                                                       muscle)                                                          48/F                                                                              Acetominephren,                                                                           10 units, Glabella 3/8/93;                                                                 Headache pain (possibly of                                                                  Without headache pain                      Ibuprofen  16 units, Glabella 10/29/93;                                                               migraine origin) associated                                                                 for the almost 11/2                                   16 units, Crow's feet                                                                      with onset of menstrual                                                                     years since the first                                 10/29/93;   cycle.       injection. Pt. reported                               20 units, Crow's feet    that her headache                                     3/25/94;                 symptoms had                                          16 units, Glabella 8/3/94;                                                                              diminished before                                     20 units, Crow's feet    flaccid paralysis of                                  8/3/94;                  injected muscles was                                  20 units, Glabella 10/24/94                                                                             induced. Pt.                                          (Forehead and Crow's feet                                                                               experienced mild                                      injections not into muscle)                                                                             headache pain at left                                                          temporal site 3 days                                                           before injection on                                                            10/24/94.                               41/F                                                                              Inderal    20 units, Glabella 5/6/94;                                                                 Daily headaches for past 7                                                                  No follow up report yet                    (propanolol                                                                               14 units, Medial Forehead                                                                  years. True migraine                                                                        available.                                 HCL)▪                                                                           5/6/94;     headache - once every 3 to                                         (Latter injection not into                                                                 6 months.                                                          muscle)                                                          57/F                                                                              2 Tablets Fiorinal                                                                        10 units, Crow's feet                                                                      Pt. described headache pain                                                                 On 3/25/94, pt.                            (butalbinal)                                                                              12/4/92;    as "a crushing" pain in the                                                                 reported having no                         w/Codeine. 20 units, Crow's feet                                                                      forehead and temporal areas                                                                 headache pain for first                               3/25/94;    that occurs about 1                                                                         7 weeks after receiving                               15 units, Glabella 3/25/94                                                                 time/week and is associated                                                                 the first injection. She                              (Crow's feet injection not                                                                 with eye strain.                                                                            reported having 1                                     into muscle)             headache in the 8th                                                            week which was                                                                 "weaker" in severity                                                           than headache pain                                                             she recalled having                                                            prior to receiving the                                                         injections.                             43/F                                                                              Aspirin    12 units, Glabella 3/18/94;                                                                Daily headache pain brought                                                                 Pt. states that for first 6                           24 units, both sides,                                                                      on by stress.                                                                               weeks after Botox                                     Glabella (+4 units to both                                                                              injection on March 4,                                 sides, Glabella area)    1993, she did not                                     3/4/94;                  experience any                                        36 units, Forehead 6/7/94;                                                                              headache pain. Pt. had                                8 units, Lateral Glabella                                                                               "a few" headaches                                     6/29/94;                 after first 6 weeks, but                              20 units, Crow's feet    described them as                                     8/24/94;                 "much weaker" in                                      16 units, Glabella 9/30/94;                                                                             severity. However,                                    12 units, Medial Forehead                                                                               once muscle mobility                                  9/30/94                  (glabella) returned, the                              (Crow's feet and forehead                                                                               frequency of the                                      injections not into muscle)                                                                             patient's headaches                                                            increased.                              50/F                                                                              Acetominephren,                                                                           10 units, Glabella 2/22/93;                                                                Onset: Age 20.                                                                              Pt. reports that for 6                     cold compresses                                                                           12 units, Glabella 5/7/93;                                                                 Frequency: Regular                                                                          months after receiving                     to forehead; lie                                                                          15 units, Glabella 11/5/93;                                                                headaches 3 times per                                                                       the first injections she                   down in dark                                                                              16 units, Glabella 5/27/94                                                                 week. Migraine headache -                                                                   did not have any                           room                   1 time per month with                                                                       headaches.                                                        premonitory auras.                                   41/F                                                                              Fiorinal and                                                                              18 units, Glabella 6/29/94                                                                 For the last 7-8 years pt.                                                                  3 months after                             Fiorinal with          had migraine headaches                                                                      receiving the injection,                   Codeine▪;    several times per month with                                                                pt. reports that she has                   Demerol (meperi-       premonitory aura.                                                                           not had a migraine.                        dine HCL) at          However, pt. has had 3                     hospital with                       headaches which she                        severe attack                       describes as "mild".                    41/F                                                                              Aspirin    18 units, Glabella 3/9/94;                                                                 Headaches 1 time a week of                                                                  6 months after                                        20 units, Glabella 7/15/94                                                                 moderate severity. Area of                                                                  receiving the first                                               headache = over frontal                                                                     injection, pt. reports                                            region and forehead.                                                                        that she has not                                                               experienced a                                                                  headache.                               47/F                                                                              Ibuprofen  17.5 units, Glabella 8/3/94;                                                               Frequent headaches                                                                          Patient complained of                                 20 units, Crow's feet                                                                      described as a dull ache                                                                    headache at injection                                 9/30/94;    over forehead, temporal                                                                     site for first 2 days. As                             20 units, Bilateral Temporal                                                               areas and back of head. Pt.                                                                 of 9/16/94, still having                              9/30/94     also reports some pain in the                                                               daily headaches.                                      (Crow's feet and temporal                                                                  temporal mandibular joint.                                                                  However, patient                                      injections not into muscle)                                                                             states a decrease in                                                           severity. She still has                                                        movement in the                                                                glabella area.                                                                 As of 10/7/94: After                                                           injection on 9/30/94                                                           (given to temporal                                                             region), pt. reports                                                           headache in forehead                                                           area eliminated. TMJ                                                           pain also described as                                                         being "improved".                       37/M                                                                              Aspirin;   20 units, Crow's feet                                                                      Age of onset: 28 years.                                                                     As of 10/7/94: pt.                         acetominephen;                                                                            10/23/92;   Frequency: about 2 times a                                                                  reports having a "mild"                    Percodan   29 units, Crow's feet                                                                      week.        headache once every                        (oxycodone 3/18/93;    Signs and Symptoms:                                                                         few weeks after                            HCL)†                                                                              8 units, Crow's feet 7/9/93;                                                               Patient reports that she feels                                                              receiving first                                       17.5 units, Glabella 7/9/93;                                                               pain in her forehead and                                                                    injection.                                            20 units, Crow's feet                                                                      back of head.                                                      11/11/93;   Measures taken for relief:                                         15 units, Glabella 12/22/93;                                                               dark room, cold compresses,                                        18 units, Glabella 8/3/94;                                                                 Aspirin, Tylenol, Percodan.                                        (Crow's feet injections not                                                    into muscle)                                                     54/F                                                                              Imitrex    16 units, Glabella 8/26/94;                                                                Age of onset: 4 years.                                                                      As of 9/16/94: After                       (sumatriptan                                                                              10 units, Right Suboccipital                                                               Frequency: Daily.                                                                           initial injection pt.                      succinate);                                                                               9/30/94:    Diagnosed as migraine.                                                                      reported a general                         Darvon     20 units, Bilateral Temporal                                                               Precipitating events: heat,                                                                 decrease in headache                       (propoxyphene                                                                             9/30/94;    using computer, chocolate,                                                                  intensity and no                           HCL)∘. Taking                                                                 10 units, Left Suboccipital                                                                stress, allergies to pollen.                                                                headache pain in                           Imitrex during                                                                            9/30/94     Signs and Symptoms: Pain                                                                    glabella area. After                       treatment  (Latter three not into                                                                     in back of neck and flashing                                                                second injections (R.                                 muscle)     lights. Reports 12+ pain on                                                                 suboccip.), patient                                               scale of 1-10 when she                                                                      reported decrease in                                              doesn't take Elavil 25 mg.                                                                  headache pain at                                                  (Note: patient was using                                                                    injection site (back of                                           Imitrex daily + 2 Darvons +                                                                 neck on that side) and                                            10 mg of Valium daily which                                                                 a further decrease in                                             would give minimal relief to                                                                pain intensity in other                                           headache).   areas (i.e. back of                                                            eyes and other side of                                                         neck). Patient is no                                                           longer using Imitrex for                                                       pain relief. Has used                                                          Darvon or Valium to                                                            relieve headache pain                                                          only once since last                                                           injection and reports                                                          that she no longer                                                             experiences the onset                                                          of migraine on                                                                 exposure to a                                                                  precipitating event.                    45/F                                                                              Codeine,   15 units, Glabella 9/1/94;                                                                 Regular (diagnosed)                                                                         As of 9/16/94: no                          Demerol∘,                                                                     15 units, Forehead 9/1/94;                                                                 migraines and frequent                                                                      migraines since                            Fiorinal▪,                                                                      20 units, Bilateral Temporal                                                               tension headaches.                                                                          temporal injection.                        acetominephen                                                                             9/30/94     Precipitating events:                                                                       However, pt. reports                                  (Latter two not into muscle)                                                               Various things will bring on                                                                that she still has                                                headaches, such as certain                                                                  tension headaches,                                                smells, weather changes,                                                                    though describes them                                             cold, etc.   as being relatively                                                            "mild".                                 26/F                                                                              Dalmane    18.5 units, Glabella                                                                       Onset: Age 16. Regular                                                                      As of 9/19/94 Pt.                          (flurazepam                                                                               8/24/94;    (diagnosed) migraines and                                                                   reported that she still                    HCL).sub.* 20 units each, Glabella and                                                                less frequent tension                                                                       has tension headaches                                 Bilateral temporal (latter                                                                 headaches. Headache                                                                         with neck pain, but no                                not into muscle).                                                                          located in forehead and in                                                                  forehead pain. Pt. also                                           back of ears. Pt.                                                                           reports that she has                                              experiences classic migraine                                                                not had a migraine                                                aura, nausea, vomiting, loss                                                                headache since                                                    of consciousness at times.                                                                  receiving the injection.                                          Pain radiates over left side                                                                As of 10/10/94,                                                   of head.     forehead pain                                                                  returning. On 10/20                                                            had severe pain in                                                             right temporal area,                                                           nausea, blurred vision.                                                        About 2 hrs. after                                                             injections on 10/20,                                                           pain and related                                                               symptoms gone.                          28/F                                                                              Imitrex    16 units, Glabella 9/30/94;                                                                2 different types of                                                                        11/11/94: Patient                                     20 units, Bilaterally into the                                                             headaches. (1) general                                                                      states that she had no                                Crow's feet area 9/30/94                                                                   headache 2-3 times per                                                                      headache since the                                    (latter injections not into                                                                week. Starts behind eyes                                                                    treatment.                                            muscle)     and radiates to back and top                                                   of head. (2) migraine:                                                         diagnosed as migraine at                                                       age 13.                                                                        Frequency: 2 times per                                                         month. Starts behind eyes                                                      and radiates behind neck. It                                                   starts with shiny lights and                                                   visual disturbances with                                                       classic aura's. If she can                                                     take medication prior to                                                       onset it may stop it from                                                      proceeding to a full cycle.                          21/F                                                                              Aspirin    20 units, Glabella 9/20/94                                                                 Pt. has suffered from                                                                       Since injection, pt.                                              periodic migraine with light                                                                reports that she has                                              intolerance, nausea and                                                                     not experienced any                                               blurred vision for several                                                                  headache pain.                                                    years, as well as more                                                         moderate tension headache                                                      pain. Pain primarily                                                           localized in frontal and                                                       temporal areas.                                      49/F                                                                              Cafergot▪;                                                                      20 units, Glabella 9/30/94;                                                                Patient has suffered from                                                                   As of 10/14/94, pt.                        Codeine;   20 units, Bilateral Temporal                                                               "vascular migraines" for over                                                               reports that she had a                     Antidepressants;                                                                          9/30/94; 11/9/94, 20 units,                                                                21 years with pain primarily                                                                migraine on 10/6                           Beta blockers                                                                             Left Temporal                                                                              on the right side of her head.                                                              without premonitory                        (taking during                                                                            (Latter two injections not                                                                 Precipitating events: Strong                                                                symptoms that she                          treatment) into muscle)                                                                               smells, bright lights, certain                                                              described as                                                      foods such as cheese,                                                                       "diminished".                                                     herring thyramine-containing                                                                However, pt. reported                                             foods, red wine, chocolate,                                                                 having a severe                                                   caffeine. Aura and stuffy                                                                   migraine on 10/12, but                                            nose. Symptoms:                                                                             stated that the pain                                              dizziness, nausea, pain.                                                                    was only on the left                                                           side of her head. Pt.                                                          reported that she has                                                          not had any cluster                                                            headache pain since                                                            receiving second                                                               injection.                              __________________________________________________________________________ 

I claim:
 1. A method for reduction of pain associated with a migraine headache in a mammal comprising administering a therapeutically effective amount of an invertebrate presynaptic neurotoxin in a pharmaceutically safe form to the mammal.
 2. The method according to claim 1 wherein the neurotoxin is delivered to the face, cranium and neck.
 3. The method according to claim 2 wherein the presynaptic neurotoxin is delivered to one or more of the frontalis, corrugator, procerus and bilateral temporal muscles.
 4. The method according to claim 2 wherein the presynaptic neurotoxin is also delivered to the mammal's back.
 5. The method according to claim 1 wherein the presynaptic neurotoxin is administered by electromyographical injection into the muscle.
 6. The method according to claim 1 wherein the presynaptic neurotoxin is administered by injection in the area of the neuromuscular junction.
 7. The method according to claim 1 wherein the presynaptic neurotoxin is a Botulinum toxin.
 8. The method according to claim 7 wherein the Botulinum toxin is Botulinim toxin A.
 9. The method according to claim 1 wherein the presynaptic neurotoxin is a biologically active fragment of a proteinaceous toxin.
 10. The method according to claim 9 wherein the biologically active fragment is the lbc fragment of the Tetanus toxin.
 11. A method for reduction of symptoms associated with the onset or presence of a migraine headache in a mammal comprising administering a therapeutically effective amount of an invertebrate presynaptic neurotoxin in a pharmaceutically safe form to the mammal.
 12. A method for reduction of pain associated with a migraine headache in a mammal comprising administering a therapeutically effective amount of an invertebrate presynaptic neurotoxin in a pharmaceutically safe form to the mammal by delivery of the presynaptic neurotoxin to an extramuscular site of the face, cranium or neck.
 13. The method according to claim 12 wherein the neurotoxin is delivered to one or more target sites of the migraine headache pain experienced by the mammal.
 14. The method according to claim 13 wherein the presynaptic neurotoxin is delivered to one or more of the frontal, temporal and suboccipital areas of the face.
 15. The method according to claim 12 wherein the presynaptic neurotoxin is administered by perivascular injection.
 16. The method according to claim 12 wherein the presynaptic neurotoxin is administered by subcutaneous injection.
 17. The method according to claim 12 wherein the presynaptic neurotoxin is a Botulinum toxin.
 18. The method according to claim 17 wherein the Botulinum toxin is Botulinum toxin A.
 19. The method according to claim 12 wherein the presynaptic neurotoxin is a biologically active fragment of a proteinaceous toxin.
 20. The method according to claim 19 wherein the biologically active fragment is the Ibc fragment of the Tetanus toxin.
 21. A method for reduction of symptoms associated with the onset or presence of a migraine headache in a mammal comprising administering a therapeutically effective amount of an invertebrate presynaptic neurotoxin in a pharmaceutically safe form to the mammal by delivery of the presynaptic neurotoxin to an extramuscular site in the face, cranium or neck. 